Drug-induced liver injury: Towards early prediction and risk stratification

Table 2 Chemical and pharmacological properties of direct-acting anticoagulants likely to be associated with drug-induced liver injury risk in humans

	Dabigatran etexilate	Rivaroxaban	Apixaban	Edoxaban
Max daily dose (indication)1	220 (DVT prophylaxis) - 300 (NVAF)	5 (post ACS2) - 10 (DVT prophylaxis) - 20 (NVAF) - 30 (treatment of DVT/PE)	5 (DVT prophylaxis) - 20 (acute treatment of DVT/PE)	60 (NVAF and DVT)
Bioavailability1	6.50%	80%-100%	50%	62%
Protein binding	35%	> 90%	87%	55%
Cmax (ng/mL)	697 (at steady state after 400 mg/3 die)[54]	450 (multiple dose 30 mg/die)[55]	469 (single 20 mg dose)[56]	424 (90 mg daily at day 10)[57]
Lipophilicity (LogP)5	5.17	1.74	2.22	1.61
Biotransformation1	Conjugation forming 4 pharmacologically active acylglucuronides	Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds	O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety	Hydrolysis (mediated by carboxylesterase 1), conjugation or oxidation by CYP3A4/5 (< 10%)
Hepatic metabolism1	Only the prodrug is a substrate of P-gp; no induction/inhibition of principal isoenzymes of cytochrome P450	CYP3A4, CYP2J2 and CYP-independent mechanisms. Substrate of P-gp and BCRP	CYP3A4/5. Substrate of P-gp and BCRP	Substrate of P-gp
Structural alerts associated with RM formation	NO (aniline motif)[58,59]	NO (chlorothiophene and bis-anilide motifs)[42,58]	NO (para-methoxyaniline and bis-anilide motifs)[41,58]	ND (no published data in the literature)
Dose-based DILI Risk Score3	2.68	1.29	1.29	1.454
Cmax-based DILI Risk Score3	2.98	1.87	2.02	1.824

¹From official European Summary of Product Characteristics;

²Only in EU;

³Calculated based on formulas reported by Chen et al[34];

⁴Calculated based on formulas reported by Chen et al[34] and assuming no RM formation;

⁵Data obtained from Drug Bank (https://www.drugbank.ca/; source: ALOGPS). ACS: Acute coronary syndrome; BCRP: Breast cancer resistance protein; DVT: Deep vein thrombosis; NVAF: Non valvular atrial fibrillation; ND: Not determined; RM: Reactive metabolites; DITdP: Drug-induced torsade de pointes.